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Transcription factor ELF4 controls the proliferation and homing of CD8+ T cells via the Krppel-like factors KLF4 and KLF2
2009 Nature America, Inc. All rights reserved.
Takeshi Yamada1, Chun Shik Park1, Maksim Mamonkin2 & H Daniel Lacorazza1,2
Transcription factors that regulate the quiescence, proliferation and homing of lymphocytes are critical for effective immune system function. Here we demonstrate that the transcription factor ELF4 directly activated the tumor suppressor KLF4 downstream of T cell antigen receptor signaling to induce cell cycle arrest in naive CD8+ T cells. Elf4- and Klf4-decient mice accumulated CD8+CD44hi T cells during steady-state conditions and generated more memory T cells after immunization. The homeostatic population expansion of CD8+CD44hi T cells in Elf4-null mice resulted in a redistribution of cells to nonlymphoid tissue because of lower expression of the transcription factor KLF2 and the surface proteins CCR7 and CD62L. Our work describes the combinatorial effect of lymphocyte-intrinsic factors on the homeostasis, activation and homing of T cells.
A delicate balance between quiescence and homeostatic proliferation maintains the T cell pool. An emerging paradigm suggests that quiescence is an actively regulated state, rather than the default state, in the absence of proliferation-inducing signals1. Homeostatic proliferation of CD8+ T cells is an efcient mechanism for maintaining the T cell pool during aging2. However, neither the molecular mechanisms that regulate the homeostasis of CD8+ T cell nor the effect of this homeostasis on T cell activation and homing are completely understood. The identication of more negative regulators of T cell proliferation is vital for further understanding of lymphocyte homeostasis and immune responses as well as for the development of protocols of gene modulation to enhance the immunological memory generated after vaccination.
The transcription factor ELF4 (also known as MEF) is a member of the Ets family of proteins35. Reports suggest that ELF4 can function as a tumor suppressor in hematopoietic cells. ELF4 expression is downregulated in acute myelogenous leukemia, either by oncoproteins or by chromosome translocation with ERG (which encodes the transcriptional regulator ERG)68. Studies of ELF4-decient mice have shown that ELF4 induces a state of readiness in natural killer cells by activating expression of the gene encoding perforin3,9. Moreover, ELF4 controls the balance between activation and quiescence...